Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies

Adam M Gilbert; Pawel Nowak; Natasja Brooijmans; Matthew G Bursavich; Christoph Dehnhardt; Efren Delos Santos; Larry R Feldberg; Irwin Hollander; Stephen Kim; Sabrina Lombardi; Kaapjoo Park; Aranapakam M Venkatesan; Robert Mallon

doi:10.1016/j.bmcl.2009.11.051

Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies

Bioorg Med Chem Lett. 2010 Jan 15;20(2):636-9. doi: 10.1016/j.bmcl.2009.11.051. Epub 2009 Dec 5.

Authors

Adam M Gilbert¹, Pawel Nowak, Natasja Brooijmans, Matthew G Bursavich, Christoph Dehnhardt, Efren Delos Santos, Larry R Feldberg, Irwin Hollander, Stephen Kim, Sabrina Lombardi, Kaapjoo Park, Aranapakam M Venkatesan, Robert Mallon

Affiliation

¹ Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. gilbera@wyeth.com

PMID: 19969455
DOI: 10.1016/j.bmcl.2009.11.051

Abstract

Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.

MeSH terms

Binding Sites
Caco-2 Cells
Cell Line, Tumor
Crystallography, X-Ray
Fluorescence Polarization Immunoassay
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Serine-Threonine Kinases / metabolism
Purines / chemical synthesis
Purines / chemistry*
Purines / pharmacology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases

Substances

Intracellular Signaling Peptides and Proteins
Phosphoinositide-3 Kinase Inhibitors
Purines
Pyrazoles
Pyridines
pyrazolopyridine
MTOR protein, human
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases